Octyl gallate reduces ATP levels and Ki67 expression leading HepG2 cells to cell cycle arrest and mitochondria-mediated apoptosis

• Published in: Toxicology in vitro Vol. 48; pp. 11 - 25
• Main Authors: Lima, Kelly Goulart, Krause, Gabriele Catyana, da Silva, Elisa Feller Gonçalves, Xavier, Léder Leal, Martins, Léo Anderson Meira, Alice, Laura Manzoli, da Luz, Luiza Bueno, Gassen, Rodrigo Benedetti, Filippi-Chiela, Eduardo Cremonese, Haute, Gabriela Viegas, Garcia, Maria Claudia Rosa, Funchal, Giselle Afonso, Pedrazza, Leonardo, Reghelin, Camille Kirinus, de Oliveira, Jarbas Rodrigues
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-04-2018; Elsevier Science Ltd
• Subjects: Adenosine triphosphate; Amyloidogenesis; Anticancer properties; Antioxidants; Apoptosis; ATP; Cell cycle; Cell cycle arrest; Cellular manufacture; Diabetes mellitus; Hepatocellular carcinoma; HepG2 cells; Mitochondria; Octyl gallate; Protein expression; Proteins; Reduction; Swelling; MTG; dNTP; MTR; HepG2 cells; 7-AAD; Mitochondria; OG; GA; HBV; AIF; Octyl gallate; AOIs; DAD; AVOs; Cell cycle arrest; DAPI; HCC; TBARS; AO; DCFH-DA; MMP; PD; CPD; PI; HCV; TEM; ATP; Apoptosis
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2017.12.017

Octyl gallate (OG) is an antioxidant that has shown anti-tumor, anti-diabetic and anti-amyloidogenic activities. Mitochondria play an important role in hepatocellular carcinoma, mainly by maintaining accelerated cellular proliferation through the production of ATP. Thus, the mitochondria may be a target for antitumor therapies. Here, we investigated the effects of OG in the hepatocarcinoma cell line (HepG2) and the mechanisms involved. We report, for the first time, that treatment with OG for 24h inhibited HepG2 cell growth by decreasing mitochondrial activity and mass, which led to the reduction of ATP levels. This reduction in the energy supply triggered a decrease in Ki67 protein expression, leading cells to cycle arrest. In addition, treatment with two doses of OG for 48h induced loss of mitochondrial functionality, mitochondrial swelling and apoptosis. Finally, we report that HepG2 cells had no resistance to treatment after multiple doses. Collectively, our findings indicate that metabolic dysregulation and Ki67 protein reduction are key events in the initial anti-proliferative action of OG, whereas mitochondrial swelling and apoptosis induction are involved in the action mechanism of OG after prolonged exposure. This suggests that OG targets mitochondria, thus representing a candidate for further research on therapies for hepatocarcinoma.
[Display omitted]
•OG induces cell cycle arrest in the S phase and decreases Ki67 protein expression.•OG decreases mitochondrial activity and reduces cellular ATP in HepG2 cells.•Octyl gallate induces mitochondrial swelling and apoptosis in HepG2 cells.•HepG2 cells had no resistance to treatment after multiple doses.